PROJECT SUMMARY/ABSTRACT PROJECT IV: GENOMIC ANALYSES The overall theme of the Colorado Learning Disabilities Research Center (CLDRC) is that multiple different learning disabilities ? including reading disability, math disability, and attention deficit hyperactivity disorder ? frequently occur in the same individual as a result of deficits that affect multiple underlying functional domains. Some of these deficits affect a single domain such as phonological processing, and some affect multiple domains such as phonological processing and attention and processing speed. In the projects within the CLDRC, these functional domains will be characterized by their genetic and developmental characteristics and by their interactions with an individual?s environment. In Project IV, we focus on the genetic characteristics of these functional domains at the molecular level through several approaches. We hypothesize that some genetic variants specifically affect a single domain while other genetic variants affect multiple domains. To identify these genetic variants, we will continue our studies of CLDRC families through targeted sequencing in chromosomal regions in which we find genetic effects in a specific domain, and we will extend our search for genetic variants that have effects on multiple domains. We will modify methods for generating a learning disability risk score, based on genome-wide variation, that could be clinically useful and widely applicable regardless of race, ethnicity or sex. We will also examine individual and shared brain circuits that are critical for learning. We will identify the genes that help to determine how well these circuits are formed and function, and will relate these circuits and genes to the functional domains that they serve. Finally, in partnership with an on- going intervention trial for reading disability called the New Haven Lexinome Project, we will examine the genetic basis for differential rates of acquisition of reading skill, the influence of attention, and the interactions between the genetic and the environmental (instruction) effects in an ethnically diverse population of public school children. The overall goal of Project IV is to disentangle the individual and shared genetic, neurobiological, and environmental factors that underlie learning disabilities, and to foster development of useful strategies for diagnosis, for informing effective remediation and for developing interventions.